This invention relates to heterocyclic amide derivatives, or their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, pharmaceutical compositions made therefrom, and their medical use in mammals including humans. The compounds of this invention have activity as prostaglandin E2 receptor antagonists, which are useful in the treatment or alleviation of pain and inflammation, as well as other inflammation-associated disorders such as arthritis.
Prostaglandins are mediators of pain, fever and other symptoms associated with inflammation. Prostaglandin E2 (PGE2) is the predominant eicosanoid associated with inflammation. In addition, PGE2 is also involved in various physiological and/or pathological conditions such as hyperalgesia, uterine contraction, digestive peristalsis, awakeness, suppression of gastric acid secretion, blood pressure, platelet function, bone metabolism, angiogenesis and the like. Four PGE2 receptor subtypes (EP1, EP 2, EP3 and EP4) displaying different pharmacological properties have been identified and cloned. The EP4 subtype, a Gs-coupled receptor, stimulates cAMP production, and is distributed in a wide variety of tissue types suggesting a major role in PGE2-mediated biological events. Patent publications WO 96/06822, WO 96/11902, EP 752421-A1, WO3/16254, WO5/021508, and WO7/121578 disclose various compounds for the treatment of prostaglandin mediated diseases.
The characterization and therapeutic relevance of the prostanoid receptors and their most commonly used selective agonists and antagonists have been investigated: Eicosanoids: From Biotechnology to Therapeutic Applications, Folco, Samuelsson, Maclouf, and Veto eds, Plenum Press, New York, 1996, chap. 14, 137-154; Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87; and Prostaglandins and Other Lipid Mediators, 2002, 69, 557-573.
Thus, selective prostaglandin ligands, agonists or antagonists, depending on which prostaglandin E receptor subtype is being considered, have anti-inflammatory, antipyretic and analgesic properties similar to a conventional non-steroidal anti-inflammatory drug. In addition, selective prostaglandin ligands have effects on vascular homeostasis, reproduction, gastrointestinal functions and bone metabolism. Unlike NSAIDs, which are indiscriminate cyclooxygenase inhibitors, selective prostaglandin ligands may have reduced side effects. In particular, such compounds are believed to have reduced potential for gastrointestinal toxicity, reduced potential for renal side effects, reduced effect on bleeding times, and reduced induction of asthma attacks in aspirin-sensitive subjects.
Studies have shown that chronic inflammation induced by collagen antibody injection in mice is mediated primarily through the EP4 subtype of PGE2 receptors. See e.g. Journal of Clinical Investigation (2002, 110, 651-658). More recently, in Nature Medicine (Yao et. al. published online 24 May 2009), studies provided evidences that showed PGE2-EP4 signaling promotes immune inflammation through TH1 differentiation and TH17 expansion, thus suggesting that EP4 antagonism may be therapeutically useful for immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases, and allergic skin disorders.
The present invention relates to novel compounds and methods for treating prostaglandin E2 mediated diseases, and pharmaceutical compositions thereof. The compounds of the invention are structurally different from NSAIDs and opiates, and are antagonists of the pain and inflammatory effects of E-type prostaglandins. In particular, the present invention relates to novel compounds that are antagonists of the EP4 subtype of PGE2 receptors. The compounds are therefore expected to be useful in mammals including humans for the treatment of diseases or conditions mediated by the EP4 receptor, including acute and chronic pain, osteoarthritis, rheumatoid arthritis and cancer.